P01AI197052

TARGETING GERMLINE-BNABS VIA SOSIP TRIMERS - OVERALL ABSTRACT THIS HIVRAD PROGRAM PROJECT APPLICATION IS MADE IN RESPONSE TO PAR-24-037. IT CONTAINS TWO RESEARCH PROJECTS, ONE SCIENTIFIC CORE AND AN ADMINISTRATIVE CORE, UNDER THE DIRECTION OF PRINCIPAL INVESTIGATOR, JOHN P. MOORE, PHD (WEILL CORNELL MEDICINE; WCM) AND CO-PRINCIPAL INVESTIGATOR, IAN A. WILSON, PHD (THE SCRIPPS RESEARCH INSTITUTE; TSRI). THE THIRD PERFORMANCE SITE IS THE ACADEMIC UNIVERSITY MEDICAL CENTERS (AUMC), AMSTERDAM. THE GOAL OF THE PROJECT IS TO FURTHER DEVELOP STABLE, SOLUBLE, CLEAVED TRIMERIC MIMICS OF THE NATIVE ENV SPIKE (SOSIP TRIMERS) AS GERMLINE-TARGETING IMMUNOGENS FOR THE DEVELOPMENT OF VACCINES AIMED AT INDUCING BROADLY NEUTRALIZING ANTIBODIES (BNABS), AND AS ANTIGENS FOR STRUCTURAL STUDIES THAT IMPROVE TRIMER DESIGN. OUR CENTRAL HYPOTHESIS IS THAT PROTEOLYTICALLY CLEAVED, SOLUBLE, TRIMERIC FORMS OF HIV-1 ENV (SOSIP TRIMERS) ARE APPROPRIATE STRUCTURAL ANTIGENS FOR HIGH RESOLUTION X-RAY CRYSTALLOGRAPHY AND ELECTRON MICROSCOPY STUDIES, AND SUITABLE IMMUNOGENS FOR VACCINE RESEARCH AIMED AT THE INDUCTION OF BNABS. OUR INTENT IS TO USE STRUCTURE-BASED INFORMATION TO HELP DEVELOP AN EFFECTIVE, PROPHYLACTIC HIV-1 VACCINE (OR COMPONENT OF A MORE COMPLEX VACCINE) THAT IS BASED ON THE CONCEPT OF INDUCING SUFFICIENT TITERS OF BNABS. SOSIP TRIMERS HAVE THE DESIRED PROPERTIES AND CAN BE PRODUCED EFFICIENTLY, INCLUDING IN THE AMOUNTS AND QUALITIES REQUIRED FOR HUMAN CLINICAL TRIALS. WE WILL FOCUS ON THE USE OF APPROPRIATELY MODIFIED SOSIP TRIMERS THAT ARE ABLE TO INITIATE GERMLINE-BNAB LINEAGES THAT CAN THEN BE SHAPED AND POLISHED INTO MATURE ANTIBODIES WITH THE PROPERTIES POSSESSED BY BNABS. THE SAME HIVRAD PROGRAM TEAM HAS MADE EXCELLENT PROGRESS DURING THE PAST 5 YEARS, AND NOW SEEKS SUPPORT TO CONTINUE TO WORK TOGETHER. ITS RESEARCH PLAN INVOLVES THE FOLLOWING SUB-COMPONENTS. PROJECT 1: ROGIER W. SANDERS AND PJ KLASSE (WITH MARIT VAN GILS): DESIGN OF GERMLINE-TARGETING TRIMERS PROJECT 2: IAN A. WILSON (WITH ANDREW B. WARD): STRUCTURE GUIDED DESIGN AND REFINEMENT OF TRIMERS CORE B: JOHN P. MOORE: PRODUCTION OF SOSIP TRIMERS CORE A: JOHN P. MOORE: ADMINISTRATIVE SUPPORT MARIT VAN GILS (AUMC) WILL CO-LEAD PROJECT 1. ANDREW B. WARD (TSRI) WILL CO-LEAD PROJECT 2. AS WELL AS THE INTEGRAL COMPONENTS OF THE PROGRAM TEAM, WE PROPOSE TO MAINTAIN AND EXPAND AN EXTENSIVE NETWORK OF RESEARCH COLLABORATIONS, AND WE WILL CONTINUE TO PROVIDE SOSIP TRIMERS AND RELATED REAGENTS TO THE MANY SCIENTISTS WHO REQUEST OUR SUPPORT.

Weill Medical College Of Cornell University

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 100654805 United States

Single Zip Code

HIV Vaccine Research and Design (HIVRAD) Program (P01 Clinical Trial Not Allowed) (PAR-24-037)